Age-related macular degeneration (AMD) is the leading cause of legal blindness in individuals over 55. A hallmark characteristic of AMD is the buildup of deposits called drusen underneath the retinal pigment epithelium (RPE), a layer of cells that maintains the health of the retina. Another characteristic of AMD is the buildup of a pigmented material called lipofuscin in the lysosomes of RPE cells. Surprisingly little is known about the underlying molecular causes of AMD, but an increasing body of evidence suggests that inflammation may be involved. Recent work has also shown that a protein complex known as the NALP3 inflammasome can be activated by the lysosomal damage and leakage that results from the phagocytosis of indigestible material. The NALP3 inflammasome processes the inflammatory cytokine IL-12 and causes its secretion. It has been shown that components of lipofuscin, which builds up in RPE lysosomes, can damage lysosomes and cause them to leak. It is possible that this may cause activation of the NALP3 inflammasome. It is also plausible that phagocytosis of indigestible drusen deposits could cause lysosomal damage and activation of the NALP3 inflammasome. This proposal will evaluate the hypothesis that NALP3 inflammasome activation in RPE cells contributes to the development of AMD. This hypothesis will be evaluated by testing the ability of substances found in drusen or lipofuscin to cause NALP3 inflammasome activation and secretion of IL-12 in vitro. We will also test whether deleting the genes for components of the NALP3 inflammasome can reduce the severity of a mouse model of AMD. This work has the potential to provide greatly needed insight into a disease whose incidence is rapidly rising. PUBLIC HEALTH RELEVANCE: AMD is a leading cause of legal blindness in elderly populations, affecting over 1.75 million Americans29 and 30-50 million people globally2. As the average age of the United States population continues to rise, it is estimated that almost 3 million Americans will have AMD by 202029. New insights into the underlying molecular causes of AMD may identify new ways to treat or prevent this disease.